tbuckley/cabot-search huggingface dataset:
Abstract 5575: Pre-clinical validation of a LGR5-targeting CAR-T against colorectal cancer
Authors: Veronika Bandara, Stuart Mills, Emma Thompson, Lih Tan, Batjargal Gundsambuu, Silvana Napoli, Jade Foeng, Dylan McPeake, Justin Coombs, Allison Cowin, Claudine Bonder, Timothy Sadlon, Shaun McColl, Simon Barry
Journal: Cancer Research (2022)

Abstract Chimeric antigen receptor T cells (CAR-T) have demonstrated robust clinical activity against B-cell malignancies, and rapid translation to approval for use in man has inspired the search for CAR-T cells against solid tumors. Cancer stem cells are a small population of cells within a tumor that have the capacity to self-renew, differentiate, and initiate new tumors. Cancer stem cells are known to be resistant to chemotherapy and radiotherapy and are enriched in residual disease which allows relapse. Targeting cancer stem cells will reduce the tumors’ ability to generate new cells resulting in tumor remission. We have tested a novel CAR-T cell that has the potential to target cancer stem cells. Leucine-rich G protein-coupled receptor 5 (LGR5) expression is restricted to stem cell populations in multiple tissues in adults. In addition, LGR5 is a marker of cancer stem cells and LGR5+ cells are implicated in tumor progression and metastasis. We designed six lentiviral CAR-T constructs targeting the extra cellar domain of LGR5 with differing linker lengths and binding domain orientation, and tested gene delivery to purified human CD3 T cells and in vitro cytotoxicity. All constructs were expressed robustly (&amp;gt;90%), and four of six LGR5-targeting CAR-T cells showed significant antigen-specific cytotoxicity against colorectal cancer cell lines in vitro. We confirmed the on-target specificity of the LGR5 targeting CAR-T using a cell line over-expressing the LGR5 protein and antibody competition assays, which blocked cytotoxicity. Using optimized gene delivery and CAR-T manufacturing protocols, we generated pre-clinical scale batches of the four lead constructs to evaluate their potency in a pre-clinical colorectal cancer xenograft mouse model. Post expansion our cell products expressed markers of self-renewing naïve-like and central memory phenotype and three out of four LGR5-targeting CAR-T cells were able to significantly inhibit the growth of human colorectal tumors. These results suggest a CAR-T targeting LGR5 may provide long-term protection against tumor growth. Our data positions LGR5-targeting CAR-T therapy as a viable therapeutic for human metastatic colorectal cancer types with minimal off-target effects, which we now aim to test in human clinical trials. Citation Format: Veronika Bandara, Stuart Mills, Emma Thompson, Lih Tan, Batjargal Gundsambuu, Silvana Napoli, Jade Foeng, Dylan McPeake, Justin Coombs, Allison Cowin, Claudine Bonder, Timothy Sadlon, Shaun McColl, Simon Barry. Pre-clinical validation of a LGR5-targeting CAR-T against colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5575.
Abstract 3850: Supermeres are functional extracellular nanoparticles replete with cancer biomarkers and therapeutic targets
Authors: Qin Zhang, Dennis K. Jeppesen, James N. Higginbotham, Sarah E. Glass, Jeffrey L. Franklin, Robert J. Coffey
Journal: Cancer Research (2022)

Abstract Cancer-derived extracellular vesicles, including exosomes, and exomere nanoparticles, are under intense investigation for cargo that may serve as clinical biomarkers and therapeutic targets. Here, we report the discovery of a new extracellular nanoparticle, termed supemeres. Supermeres are morphologically different from exomeres as determined by fluid-phase atomic force microscopy and display distinct uptake both in vitro and in vivo. In colorectal cancer (CRC) cell-derived supermeres, TGFBI is the most abundant protein and is linked to CRC progression and survival. Supermeres are enriched with cargo involved in multiple cancers including glycolytic enzymes, AGO2, shed MET and GPC1, and miR-1246. The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab-resistance, and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential cancer-related circulating biomarkers and therapeutic targets. Citation Format: Qin Zhang, Dennis K. Jeppesen, James N. Higginbotham, Sarah E. Glass, Jeffrey L. Franklin, Robert J. Coffey. Supermeres are functional extracellular nanoparticles replete with cancer biomarkers and therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3850.
Abstract 571: Inclusion of a Dap10 costimulatory domain decreases cytokine release syndrome in chimeric antigen-expressing gamma delta T cells
Authors: Amorette E. Barber
Journal: Cancer Research (2022)

Abstract Adoptive transfer of T cells is a promising anti-tumor therapy for many cancers. To enhance tumor recognition by T cells, chimeric antigen receptors (CAR) consisting of signaling domains fused to receptors that recognize tumor antigens can be expressed in T cells. While CAR T cells can successfully treat hematopoietic malignancies, CAR T cells have not shown success in treating solid tumors. There are many factors that may enhance CAR T cell efficacy and safety for solid tumor treatment, including addition of costimulatory domains to increase T cell functions and switching the T cell type used from alpha beta to gamma delta T cells. We developed a novel CAR (chimeric PD-1, chPD1) that targets the programmed death 1 receptor (PD-1) ligands expressed on many types of solid tumors. The aim of this study was to compare anti-tumor efficacy and safety of chPD1-expressing gamma delta and alpha beta T cells in murine breast and ovarian cancer models. Inclusion of different costimulatory domains, CD28, 4-1BB, and Dap-10, in the chPD1 receptor was also compared. There were no differences in T cell viability and proliferation when comparing costimulatory domains or T cell type. Additionally, there were no significant differences in killing of murine breast and ovarian cancer cell lines. ChPD1-CD28 T cells had increased secretion of proinflammatory and cytokine release syndrome (CRS)-inducing cytokines, including IFN-gamma, IL-2, IL-6, GM-CSF, and nitric oxide, compared to chPD1-41BB and chPD1-Dap10 receptors. Additionally, alpha beta chPD1 T cells had increased cytokine secretion of inflammatory cytokines compared to chPD1 gamma delta T cells. Furthermore, while gamma delta and alpha beta T cells expressing chPD1 receptors with a Dap10 domain had similar anti-tumor efficacy in vivo, chPD1-Dap10 gamma delta T cells had the lowest serum levels of inflammatory cytokines IFN-gamma, IL-6, and GM-CSF. Therefore, inclusion of Dap10 domains in gamma delta T cells may be a safer and more efficacious option for CAR T cell therapy of solid tumors. Citation Format: Amorette E. Barber. Inclusion of a Dap10 costimulatory domain decreases cytokine release syndrome in chimeric antigen-expressing gamma delta T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 571.
Abstract 3970: Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation
Authors: Alex Martínez-Sabadell, Enrique J. Arenas, Irene Rius Ruiz, Macarena Román Alonso, Marta Escorihuela, Antonio Luque, Carlos Alberto Fajardo, Alena Gros, Christian Klein, Joaquin Arribas
Journal: Cancer Research (2022)

Abstract Elimination of cancer cells by effector immune cells represents the culmination of a complex cascade of events, and disruption of any of those events may result in resistance. T cell-engaging therapies, such as T cell bispecific antibodies (TCBs) or chimeric antigen receptors (CARs), are raising extraordinary expectations as future treatments for virtually all cancers. Encouraging these expectations, TCBs and CARs have been recently approved to treat some hematologic malignancies. In contrast, TCBs and CARs against solid tumors tested to date, have failed to show clinical efficacy. This failure prompted intense research and the subsequent identification of mechanisms of primary and acquired resistance. Different strategies are being implemented to overcome these mechanisms of resistance. All these mechanisms impinge on the ability of T cells to reach cancer cells and/or on the inhibition of T cells. However, little is known about putative intrinsic mechanisms of resistance of cancer cells. That is, mechanisms deployed by tumor cells to resist killing by fully active and correctly engaged T cells. Using in vitro and in vivo acquired resistant models to TCBs and CARs directed against HER2, we demonstrate that disruption in interferon-gamma (IFN-g) signaling in cancer cells is a mechanism of intrinsic resistance to killing by fully active, correctly engaged, T lymphocytes. Importantly, we have identified that the kinase JAK2, which transduces the signal initiated by IFN-g, is the component preferably disrupted to acquired resistance across all models used. These results unveil a novel mechanism of resistance to T-cell based therapies, and imply the potential use of JAK2 and IFN-g response as a surrogate biomarker of response to immunotherapies. In addition, they open the avenue for the screening for therapies that can overcome deficient interferon-gamma response or restore JAK2 levels, which are promising potential candidates to increase the benefits of immunotherapies. Citation Format: Alex Martínez-Sabadell, Enrique J. Arenas, Irene Rius Ruiz, Macarena Román Alonso, Marta Escorihuela, Antonio Luque, Carlos Alberto Fajardo, Alena Gros, Christian Klein, Joaquin Arribas. Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3970.
Abstract 5569: CAR-T cells with αPDL1/CD28 switch-receptor synergize radiotherapy and anti-PD1 therapy in solid tumors
Authors: Limei Yin, Wenbo Wang, Zhuoran Yao, Jianxin Xue, Ruizhan Tong, Hui Wang, Shuangsi Liao, Laduona Wang, Yue Zheng, Feifei Na, Min Yu, Xuanwei Zhang, Youling Gong, Meijuan Huang, Xianming Mo, Chong Chen, You Lu
Journal: Cancer Research (2022)

Abstract The therapeutic efficacy of CAR-T cells in solid tumors, unlike in hematologic tumor, is greatly limited by the insufficient infiltration and persistence of CAR-T cells as well as the immunosuppressive tumor microenvironment. The aim of this study was to overcome these obstacles by introducing an αPDL1/CD28 switch-receptor construct and by seeking combinatorial strategies for CAR-T cells in solid tumors. We found that in non-transduction T cells, the cytokine release and T cell proliferation were repressed in response to PD-L1 protein, while T cells that express αPDL1/CD28 switch-receptor showed enhanced functions, indicating that αPDL1/CD28 could revert PD-L1 inhibition into CD28 costimulation. CAR-T cells with αPDL1/CD28 switch-receptor showed better effector function than that of unitary CAR-T in vitro studies and significant responses in tumor-bearing mice, with more effector memory T cells infiltrated in the tumor. On this basis, PD-1 inhibitor can further enhance the efficacy and persistence of αPDL1/CD28 CAR-T cells, especially in PDL1+ tumor models. We found in vitro studies that radiotherapy increased the expression of T-cell recruiting chemokines and promoted CAR-T cell transmigration. In tumor-bearing mice, synergistic anti-tumor efficacy of mice treated with radiotherapy and αPDL1/CD28 CAR-T cells was further observed. Finally, triple therapy with radiotherapy and anti-PD1 plus αPDL1/CD28 CAR-T cells maximized antitumor responses and induced complete cures in the tumor-bearing mice. Our study suggests that αPDL1/CD28 augments the function of CAR-T cells, and the combinatorial regime of αPDL1/CD28 CAR-T cells, radiotherapy and anti-PD1 in solid tumors could be further investigated. Citation Format: Limei Yin, Wenbo Wang, Zhuoran Yao, Jianxin Xue, Ruizhan Tong, Hui Wang, Shuangsi Liao, Laduona Wang, Yue Zheng, Feifei Na, Min Yu, Xuanwei Zhang, Youling Gong, Meijuan Huang, Xianming Mo, Chong Chen, You Lu. CAR-T cells with αPDL1/CD28 switch-receptor synergize radiotherapy and anti-PD1 therapy in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5569.
Abstract 1558: Drug repurposing strategies for pancreatic cancer management
Authors: Shreyas R. Gaikwad, Sanjay K. Srivastava
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the currently the third leading cause of cancer related deaths and is projected to be the second leading cause by 2030. The difficulty in diagnosis and aggressiveness of the disease makes it a difficult-to-treat cancer. Currently, treatment of PDAC mainly involves use of standard chemotherapeutic combinations. Although effective, the current options do not always provide a benefit and patients develop resistance over time. Additionally, the adverse effect profile of standard regimen is a concern. Thus, novel agents which offer better clinical and survival response are urgently required. Drug repurposing is an effective strategy to overcome the limitations in current treatment options. Through drug repurposing, we identified the anti-cancer effects of a compound MBO in human PDAC cell lines AsPC-1, MiaPaCa-2, BXPC3, Panc-1 and SUIT-2. Further, we observed the ability of MBO to suppress colony formation in PDAC cell lines AsPC-1, MiaPaCa-2 and BXPC3. Additionally, MBO induced cell death by apoptosis in PDAC cell lines which was confirmed by Annexin V/FITC analysis using flow cytometry. MBO significantly suppressed tumor growth in a subcutaneous model of PDAC. Studies are currently ongoing to explore the mechanism of action as well as effect of MBO in orthotopic PDAC models. Citation Format: Shreyas R. Gaikwad, Sanjay K. Srivastava. Drug repurposing strategies for pancreatic cancer management [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1558.
Abstract 5840: The characteristics of TP53 germline mutations analyzed in a large-scale cohort of Chinese glioma patients
Authors: Xinyu Hong, Ximeng Zhao, Zeshang Guo, Xiaochen Yang, Bella Guo, Xiang Zhang, Tonghui Ma
Journal: Cancer Research (2022)

Abstract Backgrounds:TP53 germline mutation is well known to be the cause of Li-Fraumeni syndrome (LFS), a rare autosomal dominant cancer syndrome, characterized by predisposition of breast cancer, soft tissue carcinoma, osteosarcoma, brain cancer and etc. LFS has been reported in cases or small-scale cohorts for decades, while the characteristics of TP53 germline mutations carried by glioma patients were still less studied due to rarity. We performed large-scale retrospective research to identify TP53 germline mutations in Chinese glioma patients, which would extend the genetic knowledge of LFS related glioma. Methods:We enrolled 3325 glioma patients in this study (female=1423, male=1902). Next-generation sequencing panel targeting 825 genes was performed to identify TP53 germline mutations. Mutations were annotated pathogenic or likely pathogenic according to ACMG guidelines or referring to the literatures. Results:After annotation, 20 pathogenic or likely pathogenic germline mutations (PGMs) in TP53 were found in 3325 glioma patients. There was no statistical significance of gender ratio between all glioma patients and mutation carriers (female=6, male=14, p=0.25). The highest incidence rate of PGMs occurred in glioblastoma (n=16, 80.0%), followed by anaplastic astrocytoma (n=2, 10.0%), oligodendroglioma (n=1, 0.5%) and diffuse midline glioma (n=1, 0.5%). Significant difference of onset age between TP53 mutation carriers and non-carriers was pronounced (22.90YO vs 43.35YO avg, p&amp;lt;0.0001). Furthermore, the carrier rate of PGMs was prone to decrease with increasing onset age (table 1). Conclusions:This research indicated that TP53 PGMs were prone to occur in younger glioma patients, suggesting the importance of TP53 germline mutations being screened. It might be able to assist with early detection and treatment of glioma. The carrier rate of TP53 PGMs in each onset age intervals onset age glioma patient number PGM carrier number carrier rate 0-18 444 10 2.25% 19-30 263 4 1.52% 31-45 826 4 0.48% 46-55 717 1 0.14% 56-65 687 1 0.15% 66-75 337 0 0.00% 76+ 51 0 0.00% Citation Format: Xinyu Hong, Ximeng Zhao, Zeshang Guo, Xiaochen Yang, Bella Guo, Xiang Zhang, Tonghui Ma. The characteristics of TP53 germline mutations analyzed in a large-scale cohort of Chinese glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5840.
Abstract 5466: Efficacy of ASC60, an oral fatty acid synthase inhibitor, in two tumor mouse models
Authors: Jinzi J. Wu, Handan He
Journal: Cancer Research (2022)

Abstract Background: Fatty acid synthase (FASN) is a key enzyme controlling endogenous lipid biosynthesis and overexpressed in many cancers. Studies have shown that FASN inhibition can disrupt lipid synthesis in tumor cells and disrupt tumor-associated signal transduction, suggesting FASN inhibition can serve as a potential treatment for cancer. Here we report the in vivo efficacy data of ASC60, a small molecular FASN inhibitor, either as a single agent or in combination with mouse programmed cell death-1 (mPD-1) antibody in two tumor mouse models. Methods: In the MC38 mouse model, mice were inoculated subcutaneously with MC38 cells. When the average tumor volume reached approximately 62 mm3, mice were treated with ASC60 (60, and 100 mg/kg) or vehicle once a day (QD) for 3 weeks in combination mPD-1 antibody twice a week (1 mg/kg, BIW) for 2 weeks. In patient derived orthotopic xenograft (PDOX) brain metastasis mouse model, luciferase labelled breast cancer cells (LD1-2009-362541-Luc) were transplanted into the brain of nude mice. Tumor volumes were estimated by the luciferase reporter signal. When the average signal reached 4.12X107 photon/sec, mice were treated with ASC60 (20, 60, and 100 mg/kg) or vehicle QD for 4 weeks. In both mouse models, body weights and tumor volumes were measured regularly, and tumor growth inhibitions (TGI) of different groups were compared. Results: All animals showed a gradually increase in body weight during the study and no significant difference of body weight or body weight change was found among different groups. In the MC38 colon cancer mouse model, mice treated with ASC60 (60 or 100 mg/kg) in combination with mPD-1 antibody showed higher TGI values compared to those treated with mPD-1 alone (91.86%, 99.88% vs 89.84%) on Day 13, indicating combination with ASC60 would enhance the antitumor activity of mPD-1 antibody. In PDOX mouse model, mice treated with ASC60 (20, 60, and 100 mg/kg) showed dose dependent TGI values of 10.83%, 36.95% and 49.21% on Day 13 and of 6.46%, 21.27% and 30.47% on Day 27, respectively. ASC60 also showed a significant improvement in life span (51.5 days in ASC60 60 mg/kg vs 39 days in vehicle control). Conclusion: Previous in vitro testing showed that inhibition of palmitate synthesis by ASC60 was 137-fold lower in mouse than in human (IC50: 2.05 µM in mouse vs 0.015 µM in human). However, results of the present studies showed that ASC60 could suppress tumor growth and/or expand lifespan in the two tumor mouse models either alone or in combination with mPD-1 antibody. ASC60 will possibly demonstrate better efficacies in human. Citation Format: Jinzi J. Wu, Handan He. Efficacy of ASC60, an oral fatty acid synthase inhibitor, in two tumor mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5466.
Abstract 3861: Microscope-based sorting of highly motile cancer-associated fibroblasts using a photoconvertible fluorescent protein
Authors: Sieun Lee, Young-Ho Ahn
Journal: Cancer Research (2022)

Abstract In the tumor microenvironment, cancer-associated fibroblasts (CAFs) are known to play key roles in promoting cancer cell invasion and cancer progression. CAFs are also highly invasive compared with normal fibroblasts in a 3-D co-culture system with lung cancer cells. Due to CAF heterogeneity, there are various differences in cell motility even within a CAF population. To classify CAFs according to their motility, we named less motile CAFs as “static CAFs” and more motile CAFs as “motile CAFs”. To separate and isolate these static CAFs and motile CAFs from a 3-D co-culture system, CAFs were transfected with a green-to-red photoconvertible fluorescent protein, Dendra2. Dendra2-transfected CAFs at specific areas (i.e., static or motile CAFs) were UV-irradiated using a confocal microscope. CAFs with red fluorescence were then isolated by flow cytometry and were subjected to RNA sequencing. In gene ontology and gene set enrichment analyses, two types of CAFs showed significant differences in global gene expression patterns. These data suggest that heterogeneous CAFs with different motility have distinct roles in the regulation of various signaling pathways in the tumor microenvironment. Citation Format: Sieun Lee, Young-Ho Ahn. Microscope-based sorting of highly motile cancer-associated fibroblasts using a photoconvertible fluorescent protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3861.